Enamine catalysis aldehydes

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

Enantioselective -Functionalization of Aldehydes and Ketones The direct and enantiosective functionalization of enolates or enolate equivalents with carbon-, nitrogen-, oxygen-, sulfur- or halogen-centered electrophiles represents a powerful transformation of chemical synthesis and of fundamental importance to modem practitioners of asymmetric molecule constmction. Independent studies from List, J0rgensen, Cordova, Hayashi, and MacMiUan have demonstrated the power of enamine catalysis, developing catalytic enantioselective reactions such as... 

Abstract The reversible reaction of primary or secondary amines with enolizable aldehydes or ketones affords nncleophilic intermediates, enamines. With chiral amines, catalytic enantioselective reactions via enamine intermediates become possible. In this review, structure-activity relationships and the scope as well as cnrrent limitations of enamine catalysis are discnssed. 

Keywords Aldehydes and ketones Alpha-fnnctionalization Amines Enamine catalysis Organocatalysis... 

This catalytic enamine formation is limited to aldehydes and ketones as starting materials - it does not appear to be possible to prepare corresponding enamines , i.e. A,0-ketene acetals, from esters in this fashion. Nevertheless, the preparation of simple, reactive nucleophiles from normally electrophilic species, aldehydes and ketones, in a catalytic fashion sounds highly attfactive. Furthermore, the catalytic nature of these reactions allows the use of chiral amines, and the further possibility that these reactions can be rendered enantioselective. Enamines react readily with a wide variety of electrophiles, and the range of reactions that can be catalyzed by enamine catalysis is summarized in Scheme 2. 

In enantioselective enamine catalysis, the enamine can control the approach of the electrophile either by the steric bulk of the enamine or by directing the electrophile with an activating group. As can be readily observed with relatively unreactive electrophiles, such as aldehydes, ketones or imines, additional assistance for catalysis can be provided by suitably positioned hydrogen bond donors and/or other acids (Scheme 6) [46]. 

Aldehydes bearing a-hetero substituents also typically afford anti products, and the general solution to syn selective a-heteroatom substituted aldehyde-aldehyde aldol processes via enamine catalysis also still remains to be discovered. Nevertheless, the anti process is remarkably useful because a variety of highly substituted aldehydes can be accessed in a single operation using only very inexpensive catalysts, such as proline 6 or the phenylalanine-derived imidazohdinone 46 (Scheme 21) [114, 116, 117, 119-121, 188]. 

Direct catalytic intermolecular a-allylic alkylation of aldehydes and cyclic ketones has been achieved using a one-pot combination of a transition metal catalyst, Pd(PPh3)4, and an organocatalyst a secondary amine which facilitates enamine catalysis.300... 

A simple method for the direct catalytic allylic alkylation of aldehydes and cyclic ketones has been developed.26 The direct catalytic highly chemo- and regio-selective intermolecular a-allyhc alkylation reaction has been mediated by an unprecedented combination of palladium and enamine catalysis which furnishes a-allylic alkylated aldehydes and cyclic ketones in high yield. 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

Enamine catalysis often delivers valuable chiral compounds such as alcohols, amines, aldehydes, and ketones. Many of these are normally not accessible using established reactions based on transition metal catalysts or on preformed enolates or enamines, illustrating the complimentary nature of organocatalysis and metallocatalysis. 

S.C. PanandB. List s paper spans the whole field of current organocat-alysts discussing Lewis and Brpnsted basic and acidic catalysts. Starting from the development of proline-mediated enamine catalysis— the Hajos-Parrish-Eder-Sauer-Wiechert reaction is an intramolecular transformation involving enamine catalysis—into an intermolecular process with various electrophilic reaction partners as a means to access cY-functionalized aldehydes, they discuss a straightforward classification of organocatalysts and expands on Brpnsted acid-mediated transformations, and describe the development of asymmetric counteranion-directed catalysis (ACDC). 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Mangion, I. K., Northrup, A. B., MacMillan, D. W. C. (2004). The Importance of Iminium Geometry Control in Enamine Catalysis Identification of a New Catalyst Architecture for Aldehyde—Aldehyde Couplings. Angewandte Chemie, 116, 6890-6892. 

A wide variety of carbon nucleophiles have been successfully used in the organocatalytic asymmetric inter- and intramolecular Michael addition to different a,p-unsaturated systems. Among them, the addition of aldehydes to diverse Michael acceptors such as, a,p-unsaturated ketones, alkylidene malonates, P-nitrostyrenes, and vinyl sulfones, is one of the most studied reactions. Enamine catalysis is the most frequently employed chiral activation found in the literature. 

OxidatiV0 Enamine Catalysis. The oxidative transformation of enam-ines derived from saturated aldehydes into a,(3-unsaturated iminium ions by dehydrogenation has been independently disclosed in 2011 by Li, Wang, and co-workers [108] and by Hayashi and co-workers [109]. This chemistry provides an alternative procedure to the standard iminium catalysis, which relies on the use of a,(3-unsaturated aldehydes. Both research groups used diphenylprolynol trimethylsilyl ether as the chiral amine catalyst but while Wang employs o-iodoxybenzoic acid (IBX) as the stoichiometric oxidant [108], Hayashi s procedure relies on the use of 2,3-dichloro-5,6-dicyanoquinone (DDQ) as the oxidant [109]. This oxidation can be performed in the presence of a suitable nucleophile... 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

The first organocatalytic asymmetric Michael addition of unmodified aldehydes with nitroalkenes was reported by Barbas and co-workers [4]. In light of the concept of enamine catalysis, many chiral amines have been screened and (5)-2-(morpho-linomethyl)pyrrolidine 1 (Scheme 5.1) proved to be an effective catalyst to furnish the 7-formyl nitro products in high yields (up to 96%) with moderate enantiose-lectivity (up to 78%). Encouraged by this pioneering research on using chiral secondary... 

One of the first highly enantioselective examples of multicomponent cascade reactions in orgnocatalysis was developed by Enders et al. [62] in 2006. In this report they describe an asymmetric organocatalytic triple cascade reaction for the construction of tetrasubstituted cyclohexenecarbaldehydes (93) starting from from enals (15), nitroalkenes (28), and enolizable aldehydes (94) (Scheme 10.27). In this work, they did the sequential creation of three bonds by a high enantioselective combination of enamine-iminium-enamine catalysis for a triple cascade reaction. 

SCHEME 11.3. Silyl-protected diaryl prolinol (7)-catalyzed a-amination of a-unbranched aldehydes with azodicarboxylate esters via enamine catalysis. 

The seminal papers describing asymmetric a-fluorination of saturated aldehydes mediated by enamine catalysis were simultaneously disclosed by the groups of... 

SCHEME 13.8. Enantioselective a-fluorination of aldehydes via enamine catalysis. 

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